Process and intermediate compounds for the preparation of pyrrolidines

ABSTRACT

Processes for the preparation of pyrrolidones (7 and 8) and pyrrolidines (9 and 10) from tri-O-acetyl-D-erythro-4-pentulosonic acid esters are described. The compounds are aza sugar analogs of D-ribofuranoside and are intermediates to drugs which regulate nucleoside and nucleic acid synthesis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of Application Ser. No. 09/630,765, filed Aug. 2,2000.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

None

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to the preparation of pyrrolidines,preferably chiral, from tri-O-acetyl-ketopentulosonic acid methylesters. In particular the present invention relates to the preparationof 3,4-dihydroxy-5-hydroxymethyl pyrrolidines (1,4-dideoxy-1,4-iminopentitols) which can be substituted or unsubstituted in the N position.

(2) Description of Related Art

Aza-sugar analogs of D-ribofuranosides are important targets for thesynthesis of drugs that regulate nucleic acid synthesis.(3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone is an importantaza-sugar intermediate.

The current routes (Fleet, G. W.J., et al., Tetrahedron 44(9) 2637-2647(1988); and Fleet, G. W. J., et al., Tetrahedron 44 (9) 2649-2655(1988)) to 1,4-dideoxy-1,4-imino-D-ribitol (a pyrrolidine) and itsderivatives employ hexose sugars and require the removal of 1 carbonatom (usually by an oxidative process) that is difficult on large scale.One of the methods uses the L-gulono lactone which is a rare sugar andnot a regular article of commerce available in significant quantities.There is no relatively simple and economic synthesis available.

OBJECTS

It is therefore an object of the present invention to provide novelintermediates and processes for the preparation of hydroxylatedpyrrolidines, preferably chiral, as analogs of D-ribofuranoside. It isfurther an object of the present invention to provide a process which isrelatively easy to perform and economical. These and other objects ofthe present invention will become increasingly apparent by reference tothe following description and the drawings.

SUMMARY OF THE INVENTION

The present invention relates to the preparation of a first intermediateto the pyrrolidines by a process for the preparation of a2,3,5-tri-O-acetyl-4-ketopentulosonic acid-1-methyl ester whichcomprises:

(a) reacting a pentose sugar with methanol in the presence of an acid toform a 1-methyl pentose sugar;

(b) reacting the 1-methyl pentose sugar with acetic anhydride in thepresence of an amine to form a 1-methyl-2,3,5-tri-O-acetyl pentosesugar; and

(c) reacting the 1-methyl-2,3,5-tri-O-acetyl 1-methyl pentose sugar withan oxidizing agent to form the 2,3,5-tri-O-acetyl-4-ketopentulosonicacid-1-methyl ester.

In particular the present invention relates to a process for thepreparation of 2,3,5-tri-O-acetyl-D-erythro-4-pentulosonic acid methylester which comprises:

(a) reacting D-ribose with an acidic solution of methanol to form1-methyl D-ribofuranoside;

(b) reacting the 1-methyl D-ribose with acetic anhydride in the presenceof pyridine to form 1-methyl-2,3,5 tri-O-acetyl-D-riboside in thereaction mixture; and

(d) reacting 1-methyl-2,3,5-tri-O-acetyl-D-riboside with an oxidizingagent to form the 2,3,5-tri-O-acetyl-D-erythro-4-pentulosonic acidmethyl ester. The oxidizing agent is preferably chromium trioxide inacetic anhydride. The process is specifically shown in Scheme III.

The present invention also relates to a process for the preparation of asecond intermediate to the pyrrolidines which is a process whichcomprises:

(a) reacting tri-O-acetyl-4-pentulosonic acid methyl ester withhydroxylamine, an amine or an ammonium ion in the presence of pyridinewith the hydroxylamine to form an oxime or imine of the formula:

wherein R is selected from the group consisting of acyloxy, alkyloxy,hydroxyl, alkyl, aryl and hydrogen and R₁ to R₃ are hydrogen or aprotecting group;

(b) separating the oxime or imine from the reaction mixture. Thereaction is conducted in a non-reactive solvent with an amine base atlow temperatures −10° C. to 10° C. and then poured over ice containingan acid to trap the excess amine base or hydroxylamine. In this and thefollowing reactions, R preferably contains 0 to 10 carbon atoms and R₁contains 0 to 10 carbon atoms. R and R₁ are generally groups which arenon-labile under the reaction conditions.

The present invention also relates to a process for the preparation of athird intermediate to the pyrrolidines which is a process for thepreparation of a pyrrolidone lactam of the formula:

which comprises reducing an oxime or imine of the formula:

with a source of singlet hydrogen (H) or a hydride to form thepyrrolidone lactam, wherein R is selected from the group consisting ofacyloxy, alkyloxy, hydroxyl, alkyl, aryl, and hydrogen, and wherein R₁to R₃ are hydrogen or a protecting group and Me is methyl. The reactionis conducted in a non-reactive solvent, preferably methanol, at −10° C.to 30° C.

The present invention also relates to a process for the preparation of a2,3,5-tri-O-acetyl-1,4-dideoxy-1,4-iminopentitol which comprises:

reacting a pyrrolidone lactam of the formula:

with a source of singlet hydrogen (H) or a hydride to form the pentitol,wherein R is selected from the group consisting of alkyl, aryl andhydrogen and R₁ to R₃ are hydrogen or a protecting group. The reactionis preferably conducted at −20 to 40° C.

The present invention also relates to a process for the preparation of alactone which comprises:

(a) reacting in a reaction mixture 2,3,5-tri-O-acetyl-4-pentulosonicacid or ester with a hydride or hydrogen and a catalyst to produce2,3,5-tri-O-acetyl-pentonic acid or ester in a reaction mixture; and

(b) reacting the 2,3,5-tri-O-acetyl-pentonic acid or ester with an acidin water to form a lactone. A preferred lactone is L-lyxono-γ-lactone.

The present invention also relates to a process for the preparation of a1,4-dideoxy-1,4-imino pentitol which comprises:

(a) reacting tri-O-acetyl -4-pentulosonic acid methyl ester in methanolammonium acetate and acetic acid in the presence of a hydride reducingagent to form an ammonium compound which spontaneously cyclizes to alactam;

(b) reacting the lactam with a hydride to form 2,3,5-tri-O-acetyl1,4-dideoxy-1,4-imino pentitol; and

(c) deacylating the tri-O-acetyl-1,4-dideoxy-1,4-iminopentitol to formthe 1,4-dideoxy-1,4-iminopentitol.

The present invention also relates to a process for the preparation of1,4-dideoxy-1,4-aminopentitol which comprises:

(a) reductive cyclization of tri-O-acetyl-4-amino pentonic acid methylester with a reducing agent to form 2,3, 5-tri-O-acetyl 1, 4-dideoxy-1,4-iminopentitol via an intermediate lactam; and

(b) deacylating the 2,3,5-tri-O-acetyl-1,4-dideoxy-1, 4-iminopentitol toform 1, 4-dideoxy-1, 4-imino pentitol.

The present invention also relates to a pentulosonic acid methyl esterwhich comprises:

where R₁ to R₃ is a protecting group or hydrogen and Me is methyl.

The present invention also relates to a pentulosonic acid methyl esteroxime or imine of the formula

wherein R is selected from the group consisting of acyloxy, alkoxy,hydroxyl, alkyl, aryl and hydrogen, R₁ to R₃ are protecting groups orhydrogen and Me is methyl.

The present invention also relates to a pyrrolidone of the formula:

wherein R₁ to R₃ is a protecting group or hydrogen, and R is selectedfrom the group consisting of acyloxy, alkyloxy, hydroxy,alkyl, aryl andhydrogen.

The present invention also relates to a pyrrolidine of the formula:

where R is selected from the group consisting of acyloxy, alkyloxy,hydroxy, alkyl, aryl and hydrogen and R₁ to R₃ is a protecting group.

The specific novel compounds are:

2,3,5-Tri-O-acetyl-D-erythro-4-oximyl pentulosonic acid methyl ester.

2,3,5-Tri-o-acetyl-D-erythro-4-pentulosonic acid methyl ester.

3,4-Dihydroxy-5-hydroxymethyl-2-pyrrolidone.

(3R,4R,5R)-3,4-Dihydroxy-5-hydroxymethyl-2-pyrrolidone.

2,3,5-Tri-O-acetyl-1,4-Dideoxy-1,4-imino-D-ribitol.

2,3,5-Tri-O-acetyl-4-amino-4-deoxy-D-erythro-pentonic acid methyl ester.

N-benzyl (3R,4R,5R) 3,4-dihydroxy-5-hydroxymethyl 2-pyrrolidone.

3,4-dihydroxy-5-hydroxymethyl-N-benzyl-2-pyrrolidone.

The present invention further relates to 2,3,5-tri-O-acetyl-L-lyxonicacid methyl ester.

The present invention also relates to lyxono-γ-lactone.

The present invention also relates to L-lyxono-γ-lactone.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a proton NMR spectra for tri-O-acetyl-D-erythro-4-pentulosonicacid methyl ester 6.

FIG. 2 is a 13C NMR spectra for the compound 6 of FIG. 1.

DESCRIPTION OF PREFERRED EMBODIMENTS 1,4-dideoxy-1,4-imino pentitolsfrom triacetoxy keto pentonic acids (tri-O-acetyl pentulosonic acidesters)

The process preferably starts from the pentose D-ribose which isavailable in ton quantities and has the correct number of carbons andthe correct stereochemistries. It is much shorter and more efficientthan the other routes. Other pentoses could be used such as L-ribose, Dor L arabinose, xylose or lyxose.

1,4-Dideoxy-1,4-imino-D-ribitol is made from tri-O-acetylD-erythro-4-pentulosonic acid methyl ester or a related molecule by oneof several possible methods, the first two of which are:

(1) Reductive amination with an amine or ammonia to form a4-amino-4-deoxy pentonic acid compound that can then be cyclized to alactam. Reduction of the lactam with borane or lithium aluminum hydrideyields the desired 1,4-di-deoxy-1,4-imino-D-ribitol.

(2) Formation of an oxime which can be reduced by one of severalpossible methods to yield a 4-amino-4-deoxy pentonic acid compound thatcan then be cyclized to the lactam. Reduction of the lactam with boraneor lithium aluminum hydride will yield the desired1,4-dideoxy-1,4-imido-D-ribitol.

The tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester, the oximeand the lactam (in these examples (3R, 4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone and its N-alkylderivatives) have not been previously described. Once these compoundscan be prepared, the subsequent process step for transformation to thedesired 1,4-Dideoxy-1,4-imino-D-ribitol is in the known art.

Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester, its oxime and(3R, 4R, 5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone and itsN-benzyl derivative (formed if benzylamine is used instead of ammonia inthe reductive amination) are new compounds.

The pyrrolidines are derived from an appropriately protected (R₁ to R₃)or unprotected R₁ to R₃ is hydrogen 2,3,5-trihydroxy 4-ketopentulosonicacid esters 1 by any of several routes as shown in Scheme I.

wherein R is OH. Steps 2 and 3 combine together, where R is hydrogen oralkyl, aryl, acyloxy, alkoxy then the process follows each of the steps.Generally R₁ to R₃ is acetyl. Other groups are benzoyl, propanoyl andtrifluoroacetyl.

I t should be noted that in the present application the compounds can benumbered using the carbohydrate system wherein the carboxyl group is 1and the compounds are “pyrrolidines. Scheme I uses this carbohydratesystem to show the position of the carbons. In the pyrrolidone systemthe N in the ring is 1 in naming the various compounds. The pyrrolidonesystem is preferred for purposes of claiming the compounds.

In this scheme the protected trihydroxy 4-ketopentulosonic acid ester 1is reacted with ammonia or a primary amine or ammonium ion or withhydroxylamine to form an imine (in the former case) or an oxime 2 whereR is OH which is then hydrogenated or reduced with a metal or a metalhydride reagent to form an amine 3. The amine spontaneously cyclizes toa lactam 4 which can be reduced with borane or a hydride reagent to thedesired pyrrolidine 5.

Starting with the previously unknown compoundtri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester (R=methyl, R₁ toR₃=acetyl in Scheme I) (6), direct syntheses of the tri and dihydroxypyrrolidines (9 and 10 respectively) is obtained with the D-riboconfiguration (scheme II). The deoxygenation-of the 5-position to form10 was produced by reduction of the triacetate of the oxime (2) withhydrogen on palladium in acetic acid and thus this combination is notused as a reducing agent. Under these conditions the amino group wasalso introduced by reduction of the oxime 2. The amine cyclized to formthe intermediate amide 8 (lactam) which was reduced to the pyrrolidine10 with borane or lithium aluminum hydride. Deoxygenation of the5-position did not occur if the molecule was deactylated first or if animine was used instead of an oxime for introducing the nitrogen.

Tri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester (6) was preparedby two routes as outlined in Schemes III and IV.

In the first route (Example 1, Scheme III), D-ribose is converted to amixture of its α and β furanosides by treatment with methanol in thepresence of a catalytic amount of sulfuric acid. The methyl glycosidesare peracetylated and then oxidized with chromium trioxide in aceticanhydride (Example 2). This yields theTri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester (6) in very purestate as evidenced by the proton (FIG. 1) and 13C NMR spectra (FIG. 2).

In the second route (Example 6, Scheme IV) the peracetylated glycosidesare oxidized with ozone to give the 2,3,5-triacetyl aldonic acid methylester which is then oxidized to thetri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester 6by treatmentwith DMSO and acetic anhydride or DMSO and trifluoroacetic anhydride.

The pentulosonic acid methyl ester 6 can be converted to the pyrrolidinenucleus by several routes:

(1) Conversion to the oxime 2 and reduction to the 4-amino-4-deoxy ester3 with hydrogen Pd/C with concomitant deoxygenation at the 5 positionfollowed by cyclization to form 10 (Scheme II) where R=H and R₁=R₂=Ac.

(2) Deacetylation by acid methanolysis, oxime 2 formation, and reductionwith Pd/C to form 7 where R=R₁=R₂=R₃=H.

(3) Reductive amination with ammonia and a reductant to form the4-amino-4-deoxy ester 3 followed by cyclization to form 7 where R=HR₁=R₂=R₃=Ac.

(4) Conversion to the oxime 2, deacetylation with hydrazine, reductionto the 4-amino-4-deoxy ester 3 with hydrogen Pd/C with concomitantdeoxygenation at the 5 position followed by cyclization to from 7 whereR=R₁=R₂=R₃=H.

5 (5) Reductive amination with benzylamine and a reductant to form the4-amino-4-deoxy ester 3 followed by cyclization to form 7 where R=Benzyland R₁=R₂=R₃=Ac.

(6) Reductive amination with 2,4-dimethoxybenzyiamine and a reductant toform the 4-amino-4-deoxy ester 3 followed by cyclization to form 11where R=Benzyl and R_(1=R) ₂=R₃=Ac.

Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6 is thus a keyintermediate in the synthesis of(3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone as a1,4-dideoxy-1,4-imino-D-ribitol (9). These compounds are valuableintermediates in the synthesis of “aza-sugar” analogs of D-ribofuranose.

The transformation of tri-O-acetyl D-erythro-4-pentulosonic acid methylester 6 and its oxime 2 to 9 via 7 and its per-O-acetate was achievedvia various chemical transformations. Typical strategies are: (1)Reduction of the oxime to an amine and cyclization to the pyrrolidonewith expulsion of methanol with reagents such as hydrogen and palladium,hydrogen and platinum, hydrogen and Raney nickel, zinc and acetic acidand sodium cyanoborohydride. (2) Reductive amination of the ketonefunction of tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6with ammonia or an amine using reagents such as sodium cyanoborohydride,sodium borohydride or hydrogen and a catalyst followed by cyclization tothe pyrrolidone. The pyrrolidone is reduced to the1,4-dideoxy-1,4-imino-D-ribitol with reagents such as lithium aluminumhydride or borane.

EXAMPLE 1 Preparation of tri-O-acetyl D-erythro-4-pentulosonic acidmethyl ester 6

There are two efficient routes to the preparation of tri-O-acetylD-erythro-4-pentulosonic acid methyl ester 6. The first route is by theoxidation of tri-O-acetyl methyl α,β-ribofuranoside with chromiumtrioxide in acetic acid/acetic anhydride. The second method is by theoxidation of tri-O-acetyl methyl α,β-ribofuranoside with ozone toproduce 2,3,5-tri-O-acetyl D-ribo-pentonic acid methyl ester which isthen oxidized with a reagent such as DMSO/TFAA or DMSO/Ac₂O.

Tri-O-acetyl methyl α, β-ribofuranoside

Procedure 1

D-ribose (100 g) was dissolved in methanol (1000 ml) and conc sulfuricacid (2 ml) added. The mixture was left at room temperature for 24 hoursand then the solvent was removed at a bath temperature of less than30-350° C. Pyridine (400 ml) was added and the mixture cooled in ice to˜5° C. Acetic anhydride (300) was then added over a 20 minute period.The mixture was allowed to come to room temperature and left there for10 hours after which the solvents were removed by rotary evaporation ata bath temperature of 45-500° C. The syrup was dissolved in ethylacetate (1000 ml) and washed twice with cold saturated sodium chloride(200 ml) containing ˜30 ml of conc HCl. After 1 wash with cold saturatedsodium chloride (100 ml), the solution was dried (sodium sulfate) andconcentrated to an oil. The crude tri-O-acetyl methylα,β-D-ribofuranoside that was so produced was used without furtherpurification.

Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester

The tri-O-acetyl methyl α,β-ribofuranoside prepared from 100 g ofD-ribose by procedure 1 above was dissolved in acetic acid (1500 ml) andacetic anhydride (330 ml) added. The mixture was cooled in ice to 0-5°C. and a stream of nitrogen passed over the surface. Chromium trioxide(130 g) was added over a period of 40 minutes and the temperature neverallowed to exceed 10° C. The mixture was stirred at this temperature for1 hour then allowed to reach room temperature over a 30 minute period.It was stirred at room temperature for 5 hours. The solvents were thenrapidly removed under vacuum at a temperature not to exceed 50° C. Itwas then diluted with 2000 ml of ethyl acetate, stirred vigorously for30 minutes and filtered. The filter cake was washed with a further 500ml of ethyl acetate. The combined ethyl acetate extracts was washed with2×300 ml of cold water, dried and the solvent removed to yield thedesired product in over 92% yield (>92% pure by NMR spectroscopy). ¹HNMR in chloroform, 2.0-2.3 (3×3H singlets), 4.8 (dd, 2H, J=12 Hz), 5.61(s, 1H), 5.71 (s, 1H). ¹³C NMR 30-31 ppm (3 signals), 53.2, 66.8, 71.3,76.0, 166.7, 169.5, 170.5, 197.8.

Preparation of tri-O-acetyl D-erythro-4-pentulosonic acid methyl esteroxime (2), where R=H and R₁ to R₃=acetyl

Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester (5.5 g) wasdissolved in pyridine (16 ml) and the solution cooled to 0° C.Hydroxyamine hydrochloride (2 g, 29 mmol) was added and the mixture waskept at 0° C. for a further 15 minutes and then at room temperature for2 hours. It was poured into ice containing 18 ml of concentrated HCl(sufficient to neutralize the pyridine) and extracted with 3 times with60 mol of chloroform. The combined chloroform extracts were washed oncewith 15 ml of cold saturated sodium chloride, dried (anhydrous sodiumsulfate) and concentrated to yield a colorless syrup which slowly formedwhite crystals. Yield—5.7 g (97%). 13 C NMR-(d-chloroform) 21.0, 53.5,57.8, 62.0, 68.3, 70.8, 72.0, 151.6, 168.0, 170.1, 171.1, 172.0.

EXAMPLE 3 N-benzyl(3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone

Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6 (15.2 g) wasdissolved in methanol (85 ml) and acetic acid (3.1 g) and benzylamine(5.4 g) added. Sodium cyanoborohydride (3.1 g) was then added and themixture kept at room temperature for 24 hours to reduce the imine to anamine 3. Sodium bicarbonate (6 g) and water 20 ml was added and themixture heated for 4 hours at 70° C. to effect cyclization to the lactam7. The mixture was concentrated to a syrup and partitioned between ethylacetate (300 ml) and cold saturated sodium chloride (100 ml). The ethylacetate layer was recovered, dried (sodium sulfate) and concentrated toa syrup. The syrup was dissolved in methanol (200 ml) to which was addedpotassium carbonate 20 g and water 2 ml. The resulting mixture wasstirred at room temperature for 14 hours, filtered, the filtrateconcentrated and the resulting syrup dissolved in methanol (400 ml).Concentrated HCl (4.1 ml) was added. A white solid was formed. This wasremoved by filtration and the filtrate concentrated to dryness. Methanolwas added again and the solution again concentrated. This was repeatedone more time to give the crude N-benzyl pyrrolidone which can beconverted to the pyrrolidine to reduction.

EXAMPLE 4 (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidone

Procedure 1

Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester 6 (15.2 g) wasdissolved in methanol (100 ml) and ammonium acetate (3.0 g) and aceticacid (0.2 ml) added. Sodium cyanoborohydride (3.1 g) was then added andthe mixture kept at room temperature for 24 hours to reduce theammoniated compound to an amino group which are rearranged to thetri-acetylated product 4. The triacetylated product was deacetylatedwith potassium carbonate-methanol to form the pyrrolidone.

Procedure 2

Tri-O-acetyl D-erythro-4-pentulosonic acid methyl ester oxime whereinR=H and R₁ to R₃=acetyl (3.1 g) was dissolved in methanol (40 ml) andRaney nickel (0.5 g) added. The mixture was hydrogenated at 2atmospheres for 6 hours, filtered and concentrated to give the crudetriacetylated product. The product was deactylated with potassiumcarbonate-methanol to form the pyrrolidone.

Procedure 3

The oxime derivative formed above was treated with 4 equivalents ofhydrazine in methanol for 4 hours and then hydrogenated with 10% Pd/C inethanol containing 10% acetic acid at 50 psi and room temperature for 5hours. The product was deacetylated with potassium carbonate-methanol toform the pyrrolidone.

In these procedures, the intermediate steps of 3 and 4 Scheme I areby-passed to produce the tri-0-acetylated intermediate pyrrolidone andthe intermediate tri-O-acetylate pyrrolidone is then deacylated andreduced to the pyrrolidine (pentitol 5 in Scheme I).

EXAMPLE 5

The following is an additional procedure (Scheme V) for using thetri-O-acetyl-D-erythro-4-pentulosonic acid methyl ester 6 to form thepyrrolidine.

In a typical step, the 4-pentulosonic acid (30 g) is dissolved in 150 mlof methanol and 0.5 molar equivalents of sodium borohydride is addedafter the solution is cooled to 0° C. The mixture is maintained at 0-5°for 2 hours and then 4 equivalents of acetic acid are added to decomposethe borohydride. The methanol is removed by rotary evaporation. 200 mlof methanol is added and removed and this process of adding method andremoving repeated four times to remove all borate esters. The product 11is refluxed in 300 ml of methanol containing 1% HCl for 3 hours, toeffect deacylation and concentrated to effect lactonization. The crudeL-lyxono-γ-lactone 12 so obtained is converted to the iminopentitol 9using procedures such as that described by Fleet et al, citedpreviously.

EXAMPLE 6

Methyl tri-O-acetyl-α,β,D-ribofuranoside (2 g) was dissolved in ethylacetate (30 ml) and the solution was cooled to 0-10° C. Ozone was passedthrough for 2 hours at the rate of 20 mM per hour. The ethyl acetate wasthen removed and the product dissolved in dimethyl pentoxide (30 ml) andacetic anhydride (2 ml) added. The mixture was left at room temperaturefor 24 hours. The keto ester was isolated by concentration, andpartitioning between water/ethyl acetate. The product was recovered fromthe ethyl acetate layer.

It is intended that the foregoing description be only illustrative ofthe present invention and that the present invention be limited only bythe hereinafter appended claims.

I claim:
 1. A pentulosonic acid methyl ester oxime or imine of the formula

wherein R is selected from the group consisting of acyloxy, alkoxy, hydroxyl, alkyl, aryl and hydrogen, R₁ to R₃ are hydrogen or a protecting group and Me is methyl.
 2. 2,3,5,-Tri-O-acetyl-D-erythro-4-oximyl pentulosonic acid methyl ester.
 3. 2,3,5-tri-O-acetyl-L-lyxonic acid methyl ester. 